Combination (several drugs at the same time) versus sequential chemotherapy (same drugs given one after the other) for metastatic breast cancer

Metastatic breast cancer is not currently a curable disease but one that can be very effectively treated with chemotherapy, endocrine therapy and targeted therapies. Average survival is about two years but some women live for many years longer. It is important to investigate the best way to give chemotherapy to treat metastatic breast cancer in order to optimise survival and quality of life and to minimise the side effects from treatment.

This review investigated whether giving a combination of drugs at the same time was more effective than giving the same drugs one at a time (sequential treatment).

A literature search conducted in October 2013 resulted in 12 randomised controlled studies with 2317 patients that could be included in the analysis. The patients had metastatic breast cancer and either they had not been treated or had received one or two treatments after their diagnosis of metastatic breast cancer. The primary outcomes were overall survival and progression-free survival (time from randomisation to the time of disease progression). Secondarily, we compared the degree the tumour shrunk in response to chemotherapy (overall response rate), toxicity and quality of life.

There was no difference in overall survival between the two groups but we found that when drugs were given one at a time there maybe more time before the tumours grew back again (longer progression-free survival). However, combination chemotherapy caused tumours to shrink more, although this did not result in longer survival than when using sequential chemotherapy. Rates of febrile neutropenia (infection) were higher in the combination arm but there was no difference in the rates of neutropenia (low white blood cells). There was no difference in quality of life between the two groups but there were only three trials that reported this information. Quality of life should be included as an outcome in future trials addressing this question. Overall, the studies did not consistently report the way patients were randomised and this may be a source of bias in the results.

Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

Authors' conclusions: 

There is weak evidence that sequential single agent chemotherapy has a positive effect on progression-free survival, whereas combination chemotherapy has a higher response rate and a higher risk of febrile neutropenia in metastatic breast cancer. There is no difference in overall survival time between these treatment strategies, both overall and in the subgroups analysed. In particular, there was no difference in survival according to the schema of chemotherapy (giving chemotherapy on disease progression or after a set number of cycles) or according to the line of chemotherapy (first-line versus second- or third-line). Generally this review supports the recommendations by international guidelines to use sequential monotherapy unless there is rapid disease progression.

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Background: 

Combination chemotherapy can cause greater tumour cell kill if the drug dose is not compromised, while sequential single agent chemotherapy may allow for greater dose intensity and treatment time, potentially meaning greater benefit from each single agent. In addition, sequentially using single agents might cause less toxicity and impairment of quality of life, but it is not known whether this might compromise survival time.

Objectives: 

To assess the effect of combination chemotherapy compared to the same drugs given sequentially in women with metastatic breast cancer.

Search strategy: 

We searched the Cochrane Breast Cancer Group Specialised Register, using the search terms "advanced breast cancer" and "chemotherapy", MEDLINE and EMBASE on 31 October 2013. The World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov were also searched (22 March 2012).

Selection criteria: 

Randomised controlled trials of combination chemotherapy compared to the same drugs used sequentially in women with metastatic breast cancer in the first-, second- or third-line setting.

Data collection and analysis: 

Two authors independently extracted data from published trials. Hazard ratios (HR) were derived from time-to-event outcomes where possible, and a fixed-effect model was used for meta-analysis. Response rates were analysed as dichotomous variables (risk ratios (RR)), and toxicity and quality of life data were extracted where available.

Main results: 

Twelve trials reporting on nine treatment comparisons (2317 patients randomised) were identified. The majority of trials (10 trials) had an unclear or high risk of bias. Time-to-event data were collected for nine trials for overall survival and eight trials for progression-free survival. All 12 trials reported results for tumour response. In the 12 trials there were 1023 deaths in 2317 women randomised. There was no difference in overall survival, with an overall HR of 1.04 (95% confidence interval (CI) 0.93 to 1.16; P = 0.45), and no significant heterogeneity. This result was consistent in the four subgroups analysed (risk of bias, line of chemotherapy, type of schema of chemotherapy, and relative dose intensity). In particular, there was no difference in survival according to the type of schema of chemotherapy, that is whether chemotherapy was given on disease progression or after a set number of cycles. In the seven trials that reported progression-free survival (time to first progression in the sequential arm), 637 women progressed out of the 846 women randomised. There was weak evidence of a higher risk of progression in the combination arm (HR 1.11; 95% CI 0.99 to 1.25; P = 0.08) with no significant heterogeneity. This result was consistent in all subgroups. Overall tumour response rates were higher in the combination arm (RR 1.16; 95% CI 1.06 to 1.28; P = 0.001) but there was significant heterogeneity for this outcome across the trials. In the seven trials that reported treatment-related deaths, there was no significant difference between the two arms, although the CIs were very wide due to the small number of events (RR 1.53; 95% CI 0.71 to 3.29; P = 0.28). The risk of febrile neutropenia was higher in the combination arm (RR 1.32; 95% CI 1.06 to 1.65; P = 0.01). There was no statistically significant difference in the risk of neutropenia, nausea and vomiting, or treatment-related deaths. Overall quality of life showed no difference between the two groups, but only three trials reported this outcome.

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